Cardiovascular diseases (CVDs) are the number one cause of death in U.S. They claim approximately one million lives and more than 400 billion US Dollars every year. The main cause of CVDs is arterial obstruction by the deposition of cholesterol in the inner lining of the artery. This is termed atherosclerosis (Silverthorn D U. 2004).
For the treatment of atherosclerosis, a non-invasive technique called balloon angioplasty was introduced in 1970s, which provided an attractive alternative to coronary artery bypass grafting. It used a slender collapsed balloon catheter that is inserted and inflated at the site of plaque. Upon inflation, the balloon compresses and ruptures the plaque, removing the blockage. This technique provided immediate relief to the patient. However, it was limited by the problem of abrupt closure of the artery after withdrawal of the catheter (Windecker S, et al. 2000). These challenges lead to the design of new biomedical solutions, such as bare metal stents.
To prevent the abrupt closure of artery, lattice-shaped expandable metal tubes known as bare metal stents (BMS) were introduced in 1990s. A balloon tipped catheter with a collapsed stent is inserted with a guiding catheter and guide wire. When the balloon is inflated at the plaque site, the stent expands, locks in place, and forms a scaffold holding the artery open. The use of BMS reduced the rate of restenosis compared to balloon angioplasty. While they were successful in preventing elastic recoil of the artery, BMS suffered from the problem of restenosis (i.e. re-closure of the artery) (Sheiban I, et al. 2002).
FIG. 1 shows a schematic representation of the principle mechanisms of restenosis, which include elastic recoil, negative vessel remodeling, and neointimal proliferation (Dobesh P P, et al. 2004). BMS virtually eliminates the problem of elastic recoil (Sheiban I, et al. 2002, Ozaki Y, et al. 1996) and negative vessel remodeling (Sheiban I, et al. 2002). However, the main mechanism of restenosis in BMS is neointimal hyperplasia (Violaris A G, et al. 1997). Neointimal hyperplasia is caused by endothelial denudation due to the penetration of stent struts into the vessel wall. It can be imagined that the fractured plaque exposes the thrombogenic contents of the vessel wall to the lumen, leading to a cascade of platelet adhesion, activation, and thrombosis. In addition, endothelial denudation results in the loss of antithrombotic factors. Activated platelets release factors that favor smooth muscle cell proliferation and migration. Meanwhile, smooth muscle cells also change their morphology from contractile to synthetic. This can result in smooth muscle cell migration and increased extracellular matrix (ECM) synthesis, which leads to neointimal hyperplasia and in-stent restenosis (Bauters C, et al. 1997). Hence, BMS remained limited by the high rates of in-stent restenosis. Thus, further advancements to the biomedical design of BMS were needed, such as the incorporation of localized drug delivery.
The major challenge of catheter-based drug delivery is to achieve the localization of drugs at the site of vascular injury in order to reduce the formation of neointimal hyperplasia. Thus, controlled drug delivery systems have been applied to stents, resulting in the development of drug eluting stents (DES). DES became commercially available in U.S. in 2003 (Ong A T, et al. 2005). They are coated with single or multiple bioactive agents, which are delivered in blood stream and surrounding tissues after implantation. These stents are designed to release drugs that interfere with the process of neointimal hyperplasia by targeting its biochemical pathways. Several drug delivery strategies such as diffusion controlled, dissolution/degradation controlled, and ion exchange-based methods have been investigated for DES (Acharya G, et al. 2006). DES have been shown to reduce restenosis compared with BMS (de Man F H, et al. 2007). They have been implanted in more than 6 million patients from 2004 to 2006 (Colombo A, et al. 2007).
The stent market is shared by only two drug-eluting stents: (1) Cordis CYPHER™, sirolimus-eluting stent and (2) Boston Scientific TAXUS™, paclitaxel-eluting stent. (FDA approved the CYPHER™ stent in April 2003 and TAXUS™ stent in March 2004). Both sirolimus and paclitaxel work by inhibiting the cell cycle. Sirolimus is an immunosuppressive drug that promotes kinase activation, leading to the inhibition of the cellular growth phase. Paclitaxel binds to microtubules in dividing cells and causes them to assemble, thereby preventing mitosis (Wessely R, et al. 2006). Use of these DES has shown to reduce the risk of restenosis by at least 80%, as shown by numerous randomized controlled trials (Morice M C, et al. 2002; Moses J W, et al. 2003) and meta-analyses (Roiron C, et al. 2006). However, no difference in mortality rate has been observed between DES and BMS (Roiron C, et al. 2006; Babapulle M N, et al. 2004). This can be attributed to the occurrence of late stent thrombosis or blood clots, which is an emerging cause of concern in the first generation of DES (Camenzind E, et al. 2007; Webster M W, et al. 2007; Van Belle E, et al. 2007; Jaffe R, et al. 2007; Leon M B. 2007). This late thrombosis seems to be related to discontinued antiplatelet therapy, (Zimarino M, et al. 2005) rare cases of local hypersensitivity as a reaction to the drug, and “off-label use” of DES (Win H K, et al. 2007). According to FDA standards, DES have only been approved for patients with previously untreated coronary stenosis of less than 30 mm in length and a reference vessel diameter within the range from 2.50 mm to 3.70 mm (Win H K, et al. 2007; Melikian N, et al. 2006). A study from American College of Cardiology reported “off-label use” is common and has increased in frequency over time (Rao S V, et al. 2006). In addition, studies have shown that DES cause significant delay in arterial healing due to persistent fibrin deposition and poor endothelialization when compared with the sites of BMS implantation (Finn A, et al. 2007). Angioscopic findings show incomplete neointimal covering of sirolimus-eluting stents (Kotani J, et al. 2006). Also, patient risk factors like diabetes, renal failure, and previous complications have contributed to the incidences of late thrombosis in the patients who received DES (Jaffe R, et al. 2007).
These concerns have given way to the idea of an ideal stent which should be designed to control and direct vessel repair after surgery without eliciting undesirable inflammatory response and eventually leading to a re-endothelialized vessel wall.